Autoimmune diseases can be generally attributed to an over reactive immune response wherein the host immunocytes including T- and B-cells, monocytes, macrophages, and dendritic cells (DCs) are activated to attack tissues and organs of the host. These types of progressive diseases exhibit many different phenotypic manifestations. Common autoimmune diseases include lupus (systemic lupus erhythematosus or SLE), multiple sclerosis (MS), rheumatoid arthritis (RA), psoriasis and Type 1 diabetes mellitus. Less common autoimmune diseases include Ankylosing spondylitis, Crohn's disease, Graves' disease, Guillain-Barré syndrome, and Sjögren's syndrome. In all autoimmune diseases referred to hereinabove, the debilitating symptoms are a result of an overactivated host immune system assailing host cells, tissues and organs.
Lupus is a condition wherein the adaptive immune system systematically attacks the host organs including kidney, lung, liver, peripheral and central nerve system and blood vessels. It is more prevalent in women, affecting about 1.5 million Americans today.
Multiple sclerosis, known as disseminated sclerosis or encephalomyelitis disseminate, is an ailment caused by the loss of fatty myelin sheaths around the axons of the brain and spinal cord. The loss of myelin is due to attack of the host immune systems. It is also more common in women, affecting about 400,000 Americans today.
Rheumatoid arthritis is a systemic autoimmune disorder affecting 1% of the world population. The chronic illness of RA is three times more prevalent in women than men. The etiology of RA involves the host immune system assaulting the host joints.
Psoriasis is an erythemato-squamous inflammatory skin disorder which affects approximately 2 to 3% of the world population causing lifelong suffering through disfigurement and pruritus. Psoriasis is associated with various types of joint inflammation and arthritis, which can affect normal daily activities, such as use of hands, walking, sleeping, and sexual activity and lead to disability. Psoriasis is no longer regarded as a chronic primary dysregulation of keratinocyte proliferation and is now understood to be a systemic T-cell mediated autoimmune disease.
Type 1 diabetes mellitus, also known as IDDM or juvenile diabetes, affects more than 13,000 young people each year. Type 1 diabetes is a disease where the host immune system attacks the pancreatic insulin secreting beta-cells, thus rendering the host incapable of utilizing sugar.
The aforementioned progressive diseases exhibit a variety of debilitating symptoms which commonly lead to death in the absence of effective intervention and management. The management or treatment options are often limited to corticosteroids (e.g. prednisone) or chemotherapeutic agents (e.g. methotrexate, cyclophosphamide, mycophenolate). Unfortunately, the present treatment options are associated with deleterious side effects and have limited efficacy. Thus there is an urgent and unmet need for more efficacious and clinically viable agents for treating or preventing the progression of autoimmune diseases.
Dopaminergic functions may directly mediate the activities of immunocytes and by extension affect the integral mechanisms of autoimmune disease. Immunocytes, such as human peripheral blood mononuclear cells (PBMC) (Bergquist et al. 1994), neutrophils (Cosentino et al. 1999), and macrophages (Brown et al. 2003) synthesize dopamine which may be stored in vesicles. This process is similar to the storage of dopamine in neurons and other cells. Dopamine is a regulator of immunocyte activities through autocrine-paracrine mechanisms via dopaminergic receptors that are expressed on these immunocytes (Cosentino et al. 2007). There is experimental evidence indicating that dopamine may mediate immunological homeostasis and inflammatory responses by inducing apoptosis of certain immunocytes (Cioca et al. 2000; Josefsson et al. 1996).
The dopaminergic regulation of immunity may also be established via interaction between different immunocytes. The net result of these interactions can be either stimulatory or suppressive. Dendritic cells (DCs) are implicated in the synthesis, storage, release and uptake of dopamine. When these dopamine molecules are released, it may suppress the proliferation of T-cells when the DCs interact with T-cells (Saha et al. 2001). Dendritic cells have been proposed to play a pivotal role in the initiation and perpetuation of rheumatoid arthritis by presentation of arthritogenic antigens to T-cells (Nakano et al. 2009). However, it is possible that by preventing the reuptake functions of the DCs the enriched dopaminergic microenvironment may suppress T-cells and consequently attenuate the pathogenesis of rheumatoid arthritis.
Besides directly mediating immunity through autocrine-paracrine mechanisms of the immunocytes, dopamine may mediate the activities of immunocytes through neuroendocrine mechanisms. Prolactin is a pituitary hormone important for mammalian reproductive functions and milk generation. Prolactin is also a trophic factor of immunocytes (e.g. B-cells) where, prolactin produced by pituitary glands (neuroendocrine) and immunocytes (autocrine-paracrine), is needed for the maturation and proper function of immunocytes.
Dopamine inhibits prolactin production. Elevated levels of dopamine could therefore inhibit the maturation of immunocytes (e.g. B-cells) and consequently attenuate the pathogenesis of autoimmune diseases. In fact, bromocriptine, an ergoalkoid dopamine D2 agonist with deleterious side effects including pleural effusions (Perez-Lloret et al. 2010), is frequently used “off-label” to manage the manifestations of lupus (Walker 2001).
Specific dopamine reuptake inhibition enhances endogenous dopaminergic activity systematically and/or within surrounding specific cellular microenvironments temporally. Such enriched dopaminergic activity may attenuate the function of immunocytes and curtail their attack against the host in autoimmune diseases. Moreover, drugs with enhanced target specificity (specific dopamine reuptake inhibitors) possess reduced promiscuity resulting in reduced side effects during treatment. Thus, an efficacious and clinically viable dopamine reuptake inhibitor may be used as a therapeutic agent for managing autoimmune diseases.